: Post-stroke inflammation (PSI) is a critical determinant of damage and recovery after stroke. Increasing evidence suggests that peripheral inflammatory responses to stroke have an important role in determining neurological outcome. Many inflammatory processes are activated by ischemic stroke and lead to further damage. Mast cells (MCs) release large quantities of histamine (HA), a pro-inflammatory transmitter that enhances inflammation and contributes to neuronal death. HA-signaling after stroke in peripheral organs such as the gut, one of the major sources of HA, have not been explored. The importance of the BRAIN-GUT AXIS in response to stroke is increasingly recognized. Stroke elicits a vicious cycle of central and peripheral inflammation through bi-directional communication within the gut-brain axis. Maintaining the integrity of gut barrier function is of utmost importance to prevent bacterial translocation and sepsis, a leading cause of mortality in elderly stroke patients. Histamine release and gut MCs (gMC) activation leads to severe gut inflammation. My preliminary findings, which forms the foundation of this proposal, implicates stroke-induced gut HA receptor activation as a key mediator of brain-gut axis communication after stroke. However, the timing and of gut HA-signaling after stroke, and the potential to manipulate this axis to improve functional recovery has not been investigated. Stroke induced a histamine spike in the blood that was significantly and persistently elevated in aged versus young mice. We hypothesize that this is secondary to activation of mast cells in the gut. Inhibition of HA-signaling in the peripheral gut mucosa will lead to a suppression of both peripheral and brain inflammation, and improve functional recovery and reduce mortality in an animal model of stroke. I will test the central hypothesis that neuroinflammation results from elevated peripheral gut histamine signaling, MC degranulation, gut barrier breakdown, loss of bacterial containment and trafficking of pro- inflammatory mast cells to the brain. This will be more profound in aged mice. Aged MCs are known to be in an increased state of activation with higher levels of histamine. Thus, aging is a primary factor influencing the levels of HA. Given that aging is accompanied by chronic low-level inflammation and is a non-modifiable risk factor for stroke, I will use aged (Ag) mice to study the role of gMC-mediated histamine signaling in PSI. Preliminary data suggests that suppressing histamine receptor (HR) activation and controlling HA release in the periphery post-stroke improves outcomes. This R21 will investigate the molecular mechanisms underlying MC and HR activation in the gut as a potential therapeutic target for better recovery after stroke.